1. Field of the Invention
The invention relates generally to pharmaceuticals, and more specifically to somatostatin analogue compounds, their use and preparation.
2. Background Information
Somatostatin (somatotrophin release-inhibiting factor) was first isolated and characterized by Brazeau et al. (Brazeau, P., Vale, W., Burgus, R., Ling, N., Butcher, M., Rivier, J., and Guillemin, R., Science, 1972, 179, 77-79). Somatostatin (SRIF) is a cyclic peptide that is widely distributed throughout the body. SRIF occurs in two major forms, 14- and 28-amino acid forms. There have been five SRIF receptors identified and cloned from human tissue (sst-1 to sst-5). All five receptors are members of the G protein-linked receptor family.
SRIF is widely distributed throughout the body. It has important regulatory effects on a variety of endocrine and exocrine functions in the body. SRIF inhibits the release of several hormones, including growth hormone from the anterior pituitary, insulin and glucagon from the pancreas, gastrin from the gastrointestinal tract. It also has antiproliferative activity, and acts as a neurotransmitter, or neuromodulator in the brain. As such, SRIF has been recognized as an important nexus of a number of physiological functions that are in turn involved in various disease states. It has also been recognized that such diseases can be treated through the use of compounds/drugs that have enhanced SRIF activity, such as increased potency, or longer half-life.
An example of such a compound is Sandostatin (octreotide acetate). Sandostatin is a cyclic 8-amino acid peptide analogue of somatostatin. A long-acting release formulation of Sandostatin, known commercially as, Sandostatin Lar Deport, was approved by the United States Food and Drug Administration in 1998 for the treatment of acromegaly, and to control severe diarrhea and flushing associated with metastatic carcinoid tumors, and vasoactive intestinal peptide secreting tumors (VIPomas).
Sandostatin Lar Depot mechanism of action is mimicking SRIF. Sandostatin Lar Depot has been found to reduce and normalize levels of IGF-1 (insulin growth factor) and growth hormone. Although Sandostatin is a commercially viable and useful compound, it has the inherent disadvantage of having a peptide structure. It is recognized by those of ordinary skill in the art that the peptide compounds are generally more costly to manufacture than organic molecules, and often have undesirable pharmacologic characteristics, such as short half-life, and low solubility.
Accordingly, there are unmet needs for non-peptidic SRIF analogues that can be used for the treatment of disease states that are effected by SRIF. The present invention fulfills these needs and further provides other related advantages.